Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The adipocyte-specific hormone leptin, the product of the obese (ob) gene, regulates adipose-tissue mass through hypothalamic effects on satiety and energy expenditure. Leptin acts through the leptin receptor, a single-transmembrane-domain receptor of the cytokine-receptor family. In rodents, homozygous mutations in genes encoding leptin or the leptin receptor cause early-onset morbid obesity, hyperphagia and reduced energy expenditure. These rodents also show hypercortisolaemia, alterations in glucose homeostasis, dyslipidaemia, and infertility due to hypogonadotropic hypogonadisms. In humans, leptin deficiency due to a mutation in the leptin gene is associated with early-onset obesity. Here we describe a homozygous mutation in the human leptin receptor gene that results in a truncated leptin receptor lacking both the transmembrane and the intracellular domains. In addition to their early-onset morbid obesity, patients homozygous for this mutation have no pubertal development and their secretion of growth hormone and thyrotropin is reduced. These results indicate that leptin is an important physiological regulator of several endocrine functions in humans.
 ...
PMID:A mutation in the human leptin receptor gene causes obesity and pituitary dysfunction. 953 16

Macrophage migration inhibitory factor (MIF) has been rediscovered as a proinflammatory cytokine, pituitary hormone, and glucocorticoid-induced immunoregulator. We have recently identified the expression of MIF in adipocytes and found that tumor necrosis factor (TNF)-alpha stimulates its secretion from 3T3-L1 adipocytes. Since adipocytes are regarded as a potential source of various biologically active substances, we examined in more detail the effect of TNF-alpha on MIF expression in 3T3-L1 adipocytes in the present study. We found that TNF-alpha induced MIF mRNA in dose- and time-dependent manners. After stimulation with TNF-alpha, the amount of intracellular MIF protein was unchanged or slightly decreased, concomitant with increased release of this protein into the extracellular space. This observation indicates that TNF-alpha stimulates MIF secretion from the constitutively expressed intracellular pool of 3T3-L1 adipocytes and promotes de novo synthesis of MIF. From evaluation of the mechanism of MIF gene expression, we found that tyrosine kinase inhibitors, either genistein or herbimycin A, suppressed the MIF mRNA induction by TNF-alpha. The results suggest the possibility that upregulation of MIF mRNA expression by TNF-alpha is mediated by a tyrosine kinase-dependent pathway. Taken together, the present observations shed light on the role of MIF in the metabolism of obesity and diabetes.
 ...
PMID:Tumor necrosis factor-alpha regulates the gene expression of macrophage migration inhibitory factor through tyrosine kinase-dependent pathway in 3T3-L1 adipocytes. 953 68

Tumor necrosis factor (TNF)-alpha is postulated to play a major role in the pathogenesis of obesity-linked insulin resistance, probably resulting from an interaction with insulin signaling pathways. This cross talk has now been investigated in human adipocytes at the level of phosphatidylinositol (PI) 3-kinase, and the TNF receptors (TNFRs) mediating these processes have been identified. Equilibrium binding studies using human adipocytes from mammary tissue indicated the presence of two populations of TNFR with apparent affinity constants of 13 pmol/l and 1.6 nmol/l, respectively. Interaction of TNF-alpha with insulin signaling was determined by quantification of insulin receptor substrate (IRS)-1-associated PI 3-kinase activity. Under control conditions, PI 3-kinase was activated about 10-fold in response to insulin (10[-7] mol/l, 5 min). Preincubation of adipocytes with 5 nmol/l TNF-alpha for 15 min resulted in a 60-70% reduction of insulin action, reaching a stable inhibition (40%) after longer incubation with the cytokine. The inhibitory action of TNF-alpha was dose-dependent, already detectable at 10 pmol/l, and was correlated to inhibition of tyrosine phosphorylation of IRS-1 with an unaltered autophosphorylation of the insulin receptor beta-subunit. The modulation of insulin signaling by TNF-alpha was found to be paralleled by a comparable inhibition of insulin-stimulated glucose transport. An agonistic TNFR1 antibody completely mimicked the inhibitory action of TNF-alpha on insulin signaling, whereas at 100 pmol/l TNF-alpha, a nonagonistic p80 TNFR antibody, was shown to ameliorate the inhibitory action of the cytokine. These findings indicate that in human adipocytes, low concentrations of TNF-alpha induce a rapid inhibition of insulin signaling at the level of PI 3-kinase. We suggest that under these conditions, the p80 TNFR is essential for initiating the intracellular cross talk that involves signaling by the p60 TNFR.
 ...
PMID:Tumor necrosis factor-alpha acutely inhibits insulin signaling in human adipocytes: implication of the p80 tumor necrosis factor receptor. 956 81

Leptin is an adipocyte-derived cytokine that regulates food intake and body weight via interaction with its Ob receptor (ObR). Serum leptin levels are chronically elevated in obese humans, suggesting that obesity may be associated with leptin resistance and the inability to generate an adequate ObR response. Evidence suggests that transcriptional activation of target genes by STAT3 (signal transducer and activator of transcription) in the hypothalamus is a critical pathway that mediates leptin's action. Herein we report that activation of ObR induces the tyrosine phosphorylation of the tyrosine phosphatase SH2-containing phosphatase 2 (SHP-2) and demonstrate that Tyr986 within the ObR cytoplasmic domain is essential to mediate phosphorylation of SHP-2 and binding of SHP-2 to ObR. Surprisingly, mutation of Tyr986 to Phe, which abrogates SHP-2 phosphorylation and binding to the receptor, dramatically increases gene induction mediated by STAT3. Our findings indicate that SHP-2 is a negative regulator of STAT3-mediated gene induction after activation of ObR and raise the possibility that blocking the interaction of SHP-2 with ObR could overcome leptin resistance by boosting leptin's weight-reducing effects in obese individuals.
 ...
PMID:Enhancing leptin response by preventing SH2-containing phosphatase 2 interaction with Ob receptor. 960 Sep 17

While the causes of obesity remain elusive, the relationship between obesity and insulin resistance is a well-established fact [1]. Insulin resistance is defined as a smaller than normal response to a certain dose of insulin, and contributes to several pathological problems of obese patients such as hyperlipidemia, arteriosclerosis and hypertension. Several pieces of evidence indicate that the cytokine tumor necrosis factor a (TNF-alpha) is an important player in the state of insulin resistance observed during obesity. In this review we will try to summarize what is known about the function of TNF-alpha in insulin resistance during obesity and how TNF-alpha interferes with insulin signaling.
 ...
PMID:TNF-alpha and insulin resistance: summary and future prospects. 960 26

Obesity is associated with an increased incidence of insulin resistance, dyslipoproteinemia, and hypercoagulability. In a more recently established hypothesis of body weight control and regulation of metabolism, the adipocyte secretes leptin and locally expresses TNF-alpha, the latter being responsible for the expression of metabolic cardiovascular risk factors. TNF-a mRNA expression and TNF-alpha protein are greatly increased in adipose tissue from obese animals and humans. Elevated TNF-alpha expression induces insulin resistance by downregulating the tyrosine kinase activity of the insulin receptor and decreasing the expression of GLUT-4 glucose transporters. TNF-alpha also reduces lipoprotein lipase activity in white adipocytes, stimulates hepatic lipolysis, and increases plasminogen activator inhibitor-1 content in adipocytes. Moreover, adipocytes secrete leptin, a molecule with a secondary cytokine structure whose concentrations correlate with the amount of fat tissue. Increased leptin levels downregulate appetite and increase sympathetic activity and thermogenesis in the hypothalamus. Diet-induced weight loss reduces adipose TNF-alpha expression and serum leptin levels and is associated with improved insulin sensitivity and lipid metabolism. Although exercise has also been shown to reduce leptin levels, an influence on TNF-a expression in adipocytes or muscle cells has not yet been demonstrated.
 ...
PMID:Importance of TNF-alpha and leptin in obesity and insulin resistance: a hypothesis on the impact of physical exercise. 964 96

Leptin affects food intake and body weight by actions on the hypothalamus. Although leptin resistance is common in obesity, mechanisms have not been identified. We examined the effect of leptin on expression of the suppressors-of-cytokine-signaling (SOCS) family of proteins. Peripheral leptin administration to ob/ob, but not db/db mice, rapidly induced SOCS-3 mRNA in hypothalamus, but had no effect on CIS, SOCS-1, or SOCS-2. A leptin-dependent increase of SOCS-3 mRNA was seen in areas of hypothalamus expressing high levels of the leptin receptor long form. In mammalian cell lines, SOCS-3, but not CIS or SOCS-2, blocked leptin-induced signal transduction. Expression of SOCS-3 mRNA in the arcuate and dorsomedial hypothalamic nuclei is increased in Ay/a mice, a model of leptin-resistant murine obesity. In conclusion, SOCS-3 is a leptin-inducible inhibitor of leptin signaling, and a potential mediator of leptin resistance in obesity.
 ...
PMID:Identification of SOCS-3 as a potential mediator of central leptin resistance. 966 Sep 46

Leptin is a fat cell-derived satiety factor that regulates food intake and energy expenditure. Its effects are mediated by interactions with the leptin receptor (Ob-R) that is alternatively spliced to encode at least five isoforms(a-e), which are distributed in a wide range of tissues including the hypothalamus. Ob-R is a member of cytokine receptors and involves the JAK-STAT signal transduction system. We found Ob-R mutations in Zucker fatty rats and obese Koletsky rats and demonstrated that Ob-R dysfunction brings around hyperphagia and obesity. However we and others have not found any Ob-R mutation in human obese subjects.
 ...
PMID:[Leptin Receptor]. 970 77

In view of the recent demonstration that obesity in animals and humans is associated with an increase in tumor necrosis factor-alpha (TNFalpha) expression, that this expression falls with weight loss, and that TNFalpha may specifically inhibit insulin action, the possibility that TNFalpha may be a mediator of insulin resistance has been raised. We have undertaken this study to investigate whether serum TNFalpha concentrations are elevated in obese subjects, whether they fall after weight loss, and whether this fall parallels the fall in insulin release after glucose challenge. Obese patients (age range: 25-54, weight mean +/- SD: 96.4 +/- 13.8 kg, body mass index: 35.7 +/- 5.6 kg/m2) were started on a diet program. The mean weight fell to 84.5 +/- 11.3 (P < 0.0001) and body mass index to 31.3 +/- 4.9 (P < 0.0001). Plasma TNFalpha concentrations were markedly elevated in the obese (3.45 +/- 0.16 pg/mL), when compared with controls (0.72 +/- 0.28 pg/mL), and fell significantly (2.63 +/- 1.40 pg/mL) after weight loss (P < 0.02). The magnitude of insulin release after glucose (75 g) challenge (area under the curve) also fell significantly (P < 0.01) after weight loss. The magnitude of weight loss and fall in TNFalpha were related to basal body weight (r = 0.57, P < 0.001) and basal TNFalpha (r = 0.55, P < 0.001) concentrations, respectively, but not to each other or to the glucose-induced insulin release (area under the curve). We conclude that obesity is associated with increased plasma TNFalpha concentrations, which fall with weight loss. Because circulating TNFalpha may mediate insulin resistance in the obese, a fall in TNFalpha concentrations may contribute to the restoration of insulin resistance after weight loss, Thus, TNFalpha may be an important circulating cytokine, which may provide a potentially reversible mechanism for mediating insulin resistance.
 ...
PMID:Tumor necrosis factor-alpha in sera of obese patients: fall with weight loss. 970 67

In earlier work, we reported that genetically obese (fa/fa) Zucker rats exhibited significantly greater anorexia than did lean (Fa/Fa) Zucker rats to intracerebroventricular infusion of interleukin (IL)-1beta. Here, we investigated the fever response of obese (fa/fa) and lean (Fa/Fa) Zucker rats to intracerebroventricular microinfusion of IL-1beta as well as to the following other cytokines: IL-2, IL-6, and tumor necrosis factor-alpha (TNF-alpha). Core body temperature was monitored by a radiotelemetry system in freely moving rats. The results show that 1) both IL-1beta and IL-6 induce fevers in obese and lean rats; 2) IL-1beta induces a significantly higher fever response in obese rats than it does in lean rats; 3) IL-6 induces a significantly higher fever response in lean rats than it does in obese rats; 4) IL-2 induces a moderate fever response in lean but not obese rats; 5) TNF-alpha induces a similar fever response in obese and lean rats; and 6) the fevers induced by each effective cytokine have different time courses. Thus obese (fa/fa) and lean (Fa/Fa) Zucker rats show differential responsiveness to the intracerebroventricular microinfusion of various classes of cytokines. This suggests that genetic obesity in the fa/fa Zucker rat is associated with differential cytokine action on thermoregulatory mechanisms.
 ...
PMID:Cytokine-induced fever in obese (fa/fa) and lean (Fa/Fa) Zucker rats. 975 68


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>